MMP-7 Serum and Tissue Levels Are Associated with Poor Survival in Platinum-Treated Bladder Cancer Patients

Abstract

Chemotherapy resistance is a main cause of therapeutic failure and death in bladder cancer. With the approval of immune checkpoint inhibitors, prediction of platinum treatment became of great clinical importance. Matrix metalloproteinase-7 (MMP-7) was shown to be involved in cisplatin resistance. Therefore, tissue and circulating MMP-7 levels were evaluated in 124 bladder cancer patients who received postoperative platinum-based chemotherapy. Tissue MMP-7 levels were analyzed by immunohistochemistry in 72 formalin-fixed, paraffin-embedded chemo-naïve tumor samples, while MMP-7 serum concentrations were determined in 132 serum samples of an independent cohort of 52 patients. MMP-7 tissue and serum levels were correlated with clinicopathological and follow-up data. MMP-7 gene expression was determined by RT-qPCR in 20 urothelial cancer cell lines and two non-malignant urothelial cell lines. MMP-7 was overexpressed in RT-112 and T-24 cells by stable transfection, to assess its functional involvement in platinum sensitivity. High MMP-7 tissue expression and pretreatment serum concentrations were independently associated with poor overall survival (tissue HR = 2.296, 95%CI = 1.235–4.268 and p = 0.009; serum HR = 2.743, 95%CI = 1.258–5.984 and p = 0.011). Therefore, MMP-7 tissue and serum analysis may help to optimize therapeutic decisions. Stable overexpression in RT-112 and T-24 cells did not affect platinum sensitivity.

High Serum PD-L1 Levels Are Associated with Poor Survival in Urothelial Cancer Patients Treated with Chemotherapy and Immune Checkpoint Inhibitor Therapy

“…As MMP-7 has been shown to be able to proteolytically cleave membrane bound PD-L1 and we formerly measured serum MMP-7 concentrations in samples of patients treated with adjuvant chemotherapy ( n = 23) [ 17 ]. Here, we performed the Spearmen´s rank correlation analysis between sPD-L1 and MMP7, which revealed a significant positive correlation between the concentrations of these two proteins (rs = 0.525, p = 0.001) ( Figure S2 ).…”

“…Serum MMP-7 levels were measured using the Quantikine ELISA kit from R&D Systems (Cat.Nr. : DMP700) and published in previous work of our group [ 17 ]. To exclude a possible interference/cross reactivity between the therapeutic anti-PD-L1 antibody (atezolizumab, Tecentriq®, Roche, Basel, Suisse) and our ELISA kit, we performed an ELISA analysis with atezolizumab and pembrolizumab.…”

“…In addition, we formerly found significantly elevated urine and serum MMP-7 levels in MIBC patients present with lymph node or distant metastasis and higher pretreatment serum MMP-7 levels were significantly correlated with poor survival in platinum-treated MIBC patients [ 15 , 16 , 17 ]. As MMP-7 was shown to be capable of cleaving the ectodomain region of PD-L1 [ 18 ] and thereby may increase its levels in the blood circulation, we seek correlation of formerly determined serum MMP-7 concentrations and those of recently measured PD-L1 levels in the same serum samples.…”

Elucidation of Novel Molecular Targets for Therapeutic Strategies in Urothelial Carcinoma: A Literature Review

“…There are a handful of possible molecular mechanisms that may explain this suboptimal response to cytotoxic chemotherapy. Recent studies have revealed that UC patient differences in the expression of various proteins, such as matrix metalloproteinase-7 and syndecan-1, affect the prognosis following chemotherapy ( 7 , 8 ). Additionally, individual variations in tumor-infiltrating B-cell activity have significant prognostic value for MIBC patients ( 9 ), and long noncoding mRNAs have also been found to regulate muscle-invasive UC proliferation and resistance to chemotherapy ( 10 ).…”

Orthodenticle homeobox OTX1 is a potential prognostic biomarker for bladder cancer

“…Traditionally, relapse after radical cystectomy or advanced conditions is involved in the poor outcomes of patients [ 2 ]. Chemotherapy and surgery are the main treatment strategies for BC, and can effectively prolong the survival of patients with BC [ 3 ]. Unfortunately, almost of patients with advanced conditions will die from BC.…”